Crystalline Form of y-Aminobutyric Acid Analog

ABSTRACT

A crystalline form of a γ-aminobutyric acid analog, and methods of preparing same, are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 14/206,893, filed Mar. 12, 2014, which is acontinuation application of U.S. patent application Ser. No. 13/164,620,filed Jun. 20, 2011, now U.S. Pat. No. 8,686,034, which is acontinuation application of U.S. patent application Ser. No. 12/897,567,filed Oct. 4, 2010, which is a continuation application of U.S. patentapplication Ser. No. 12/548,200, filed Aug. 26, 2009, which is adivisional application of U.S. patent application Ser. No. 10/966,507,filed Oct. 14, 2004, which claims the benefit of priority under 35U.S.C. § 119(e) to U.S. Provisional Patent Application No. 60/511,287,filed Oct. 14, 2003, the disclosures of which are hereby incorporatedherein in their entireties.

1. FIELD

Disclosed herein is a crystalline form of an analog of γ-aminobutyricacid and methods of making the crystalline form thereof. These analogsmay be used as therapeutic agents in the treatment of certain diseasesand disorders, including, for example, neuropathic pain andpost-herpetic neuralgia.

2. BACKGROUND

In general, crystalline forms of drugs are preferred over amorphousforms of drugs, in part, because of their superior stability. Forexample, in many situations, an amorphous drug converts to a crystallinedrug form upon storage. Because amorphous and crystalline forms of adrug typically have differing physical/chemical properties, potenciesand/or bioavailabilities, such interconversion is undesirable for safetyreasons in pharmaceutical administration. A key characteristic of anycrystalline drug substance is the polymorphic behavior of such amaterial. Polymorphs are crystals of the same molecule which havedifferent physical properties because the crystal lattice contains adifferent arrangement of molecules. The different physical propertiesexhibited by polymorphs affect important pharmaceutical parameters suchas storage, stability, compressibility, density (important informulation and product manufacturing) and dissolution rates (importantin determining bioavailability). Stability differences may result fromchanges in chemical reactivity (e.g., differential hydrolysis oroxidation, such that a dosage form discolors more rapidly when comprisedof one polymorph than when comprised of another polymorph), mechanicalchanges (e.g., tablets crumble on storage as a kinetically favoredcrystalline form converts to thermodynamically more stable crystallineform) or both (e.g., tablets of one polymorph are more susceptible tobreakdown at high humidity). Solubility differences between polymorphsmay, in extreme situations, result in transitions to crystalline formsthat lack potency or are toxic. In addition, the physical properties ofthe crystalline form may be important in pharmaceutical processing. Forexample, a particular crystalline form may form solvates more readily ormay be more difficult to filter and wash free of impurities than otherforms (i.e., particle shape and size distribution might be differentbetween one crystalline form relative to other forms).

Agencies such as the United States Food and Drug Administration closelyregulate the polymorphic content of the active component of a drug insolid dosage forms. In general, the regulatory agency requiresbatch-by-batch monitoring for polymorphic drugs if anything other thanthe pure, thermodynamically preferred polymorph is marketed.Accordingly, medical and commercial reasons favor synthesizing andmarketing solid drugs as the thermodynamically stable polymorph,substantially free of kinetically favored polymorphs.

1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, (1), a prodrug of the GABA analog gabapentin (2), has highbioavailability as gabapentin when dosed either orally or directly intothe colon of a mammal (Gallop et al., International Publication No. WO02/100347). The high bioavailability makes compound (1) a valuablecomponent of oral dosage forms (including sustained-release dosageforms) useful for treating or preventing epilepsy, pain (especially,neuropathic pain and muscular and skeletal pain), depression, anxiety,psychosis, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, panic, inflammatory disease (i.e.,arthritis), insomnia, gastrointestinal disorders, hot flashes, restlesslegs syndrome, urinary incontinence or ethanol withdrawal syndrome.

Compound (1), prepared as described in Gallop et al., InternationalPublication No. WO 02/100347, is isolated as a glassy solid afterlyophilization from aqueous acetonitrile. The material obtained by thisprocess is partially or wholly amorphous and certain alkali metal saltforms are hygroscopic. However, amorphous solids and particularlyhygroscopic solids are difficult to handle under pharmaceuticalprocessing conditions because of low bulk densities and unsatisfactoryflow properties. Moreover, handling of hygroscopic solids requiresspecial techniques and equipment to obtain, for example, reproducibleamounts of active compound or solid formulation stability. Furthermore,drugs that are hygroscopic must be packaged in special containers thathave water vapor barriers thus substantially increasing the cost of suchproducts.

Accordingly, a need exists for crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid with superior physicochemical properties that may be usedadvantageously in pharmaceutical processing and pharmaceuticalcompositions.

3. SUMMARY

A crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is provided that satisfies these and other needs. Also provided arepharmaceutical compositions of a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, methods of using the crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and pharmaceutical compositions thereof to treat or prevent variousdiseases and methods of making crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid.

In a first aspect, crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid is provided that has characteristic absorption peaks (2θ) at7.0°±0.3°, 8.2°±0.3°, 10.5°±0.3°, 12.8°±0.3°, 14.9°±0.3°, 16.4°±0.3°,17.9°±0.3°, 18.1°±0.3°, 18.9°±0.3°, 20.9°±0.3°, 23.3°±0.3°, 25.3°±0.3°and 26.6°±0.3° in an X-ray powder diffractogram.

In a second aspect, pharmaceutical compositions of the crystalline formof 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid are provided. The pharmaceutical compositions comprise1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid that has characteristic absorption peaks (2θ) at 7.0°±0.3°,8.2°±0.3°, 10.5°±0.3°, 12.8°±0.3°, 14.9°±0.3°, 16.4°±0.3°, 17.9°±0.3°,18.1°±0.3°, 18.9°±0.3°, 20.9°±0.3°, 23.3°±0.3°, 25.3°±0.3° and26.6°±0.3° in an X-ray powder diffractogram and a pharmaceuticallyacceptable vehicle.

In a third aspect, methods for treating or preventing epilepsy, pain(especially, neuropathic pain and muscular and skeletal pain),depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, inflammatory disease(i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes,restless legs syndrome, urinary incontinence or ethanol withdrawalsyndrome are provided. The methods generally involve administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid that has characteristic absorption peaks (2θ) at 7.0°±0.3°,8.2°±0.3°, 10.5°±0.3°, 12.8°±0.3°, 14.9°±0.3°, 16.4°±0.3°, 17.9°±0.3°,18.1°±0.3°, 18.9°±0.3°, 20.9°±0.3°, 23.3°±0.3°, 25.3°±0.3° and26.6°±0.3° in an X-ray powder diffractogram.

In a fourth aspect, pharmaceutical compositions for treating orpreventing epilepsy, pain (especially, neuropathic pain and muscular andskeletal pain), depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic,inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders, hot flashes, restless legs syndrome, urinary incontinence orethanol withdrawal syndrome in a patient in need of such treatment orprevention are provided. The methods generally involve administering toa patient in need of such treatment or prevention a therapeuticallyeffective amount of a pharmaceutical composition of1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid that has characteristic absorption peaks (2θ) at 7.0°±0.3°,8.2°±0.3°, 10.5°±0.3°, 12.8°±0.3°, 14.9°±0.3°, 16.4°±0.3°, 17.9°±0.3°,18.1°±0.3°, 18.9°±0.3°, 20.9°±0.3°, 23.3°±0.3°, 25.3°±0.3° and26.6°±0.3° in an X-ray powder diffractogram.

In a fifth aspect, methods for making crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid that has characteristic absorption peaks (2θ) at 7.0°±0.3°,8.2°±0.3°, 10.5°±0.3°, 12.8°±0.3°, 14.9°±0.3°, 16.4°±0.3°, 17.9°±0.3°,18.1°±0.3°, 18.9°±0.3°, 20.9°±0.3°, 23.3°±0.3°, 25.3°±0.3° and26.6°±0.3° in an X-ray powder diffractogram are provided.

4. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates an X-ray powder diffractogram of crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid; and

FIG. 2 illustrates a differential scanning calorimetery thermogram ofcrystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid.

5. DETAILED DESCRIPTION 5.1 Definitions

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is administered.

“Patient” includes humans. The terms “human” and “patient” are usedinterchangeably herein.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Promoiety” refers to a form of protecting group that when used to maska functional group within a drug molecule converts the drug into aprodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the patient. In yet another embodiment, “treating” or“treatment” refers to inhibiting the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and itsseverity and the age, weight, etc., of the patient to be treated.

Reference will now be made in detail to preferred embodiments. Althoughpreferred embodiments are described, it will be understood that theinvention is not limited to those preferred embodiments. To thecontrary, it is intended to cover alternatives, modifications andequivalents as may be included within the spirit and scope of theinvention as defined by any claim(s) issuing herefrom.

5.2 Crystalline Forms of1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid and Preparation Thereof

Crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and methods of making crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid are disclosed in detail herein.

It should be understood that referral to1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid includes all substantially racemic mixtures, all possibletautomeric forms of the conventional chemical structure for thiscompound and all isotopically labeled derivatives of this compound(e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, etc.).

The starting material (i.e.,1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid) can be made according to procedures disclosed in Example 13 ofGallop et al., International Publication No. WO 02/100347 or Example 12of Gallop et al., U.S. Provisional Patent Application Ser. No.60/606,637, filed Aug. 13, 2004, entitled, “Methods for Synthesis ofAcyloxyalkyl Carbamate Prodrugs.”

In one aspect, crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid is provided. In some embodiments, crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid has characteristic absorption peaks at 7.0°±0.3°, 8.2°±0.3°,10.5°±0.3°, 12.8°±0.3°, 14.9°±0.3°, 16.4°±0.3°, 17.9°±0.3°, 18.1°±0.3°,18.9°±0.3°, 20.9°±0.3°, 23.3°±0.3°, 25.3°±0.3° and 26.6°±0.3°. In otherembodiments, crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid has characteristic absorption peaks at 7.0°±0.2°, 8.2°±0.2°,10.5°±0.2°, 12.8°±0.2°, 14.9°±0.2°, 16.4°±0.2°, 17.9°±0.2°, 18.1°±0.2°,18.9°±0.2°, 20.9°±0.2°, 23.3°±0.2°, 25.3°±0.2°, and 26.6°±0.2° in anX-ray powder diffractogram.

In some embodiments, crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid melts between about 54° C. and about 78° C. In other embodiments,crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid melts between about 58° C. and about 70° C. In still otherembodiments, crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid melts between about 62° C. and about 68° C. In still otherembodiments, crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid melts between about 62° C. and about 66° C. In still otherembodiments, crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid melts between about 63° C. and about 66° C. In still otherembodiments, crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid melts between about 64° C. and about 66° C. In still otherembodiments, crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid melts between about 63° C. and about 64° C.

In some embodiments, crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid may be prepared by first adding1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid to a solvent to form a solution or suspension. As used herein, theterms solution and suspension are used interchangeably and are meant toinclude circumstances where1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is placed in a solvent or solvent mixture regardless of solubility.The solvent used in crystallization may be either a homogenous solvent,a combination of solvents, or a solvent or solvent combination in whichthe 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid exhibits temperature dependent solubility. In general,solvents or solvent combinations in which1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is soluble within a first temperature range, and poorly solublewithin a second temperature range, can be advantageously used in themethods described herein. Mixtures of a “good” solvent and an“anti-solvent” can also be used with temperature dependentsolubilization, i.e., dissolving at elevated temperature andcrystallizing at room temperature. Examples of suitable “good” solventsinclude methanol, ethanol, 1,2-propane diol, t-butanol, n-butanol,isopropanol, acetic acid, nitromethane, acetonitrile, dimethylsulfoxide,dimethylformamide, N-methyl pyrrolidone, acetone, methyl acetate, ethylacetate, isopropyl acetate, isobutyl acetate, methyl isobutyl ketone,1,2-dimethoxyethane, tetrahydrofuran, 2-methyl tetrahydrofuran, toluene,methyl t-butyl ether, chlorobenzene, 1,4-dioxane, diethylether, cumene,o-xylene, m-xylene, p-xylene, 2-ethoxyethanol, 1,2-ethandiol, ethylformate, 2-methoxyethanol, 1-pentanol, anisole, dichloromethane, cis andtrans 1,2 dichloroethylene, chloroform, dimethylacetamide, propylacetateand mixtures thereof. Examples of suitable “anti-solvents” includealkanes such as pentane, hexane, heptane, octane, nonane, decane,undecane, dodecane, cis- or trans-decalin, cyclohexane,methylcyclohexane and mixtures thereof.

Preferably, the dissolution process is carried out at elevatedtemperature, up to and including the boiling point of the solvent orsolvent combination. Accordingly, in some embodiments,1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is dissolved in a solvent or solvent mixture with heating andoptionally, with shaking and stirring. The heated solution may be keptat elevated temperature to ensure complete dissolution of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid. The heated solution may also be filtered at elevated temperatureto remove any undissolved components.

Preferably, the solution is cooled slowly to provide crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, which may be separated from residual solvent by filtration and/ordrying under reduced pressure. In some embodiments, the solution iscooled between about 0° C. and about 25° C. Other methods, known tothose of skill in the crystallization arts, (e.g., solvent evaporation,drowning, chemical reaction, seeding with a small quantity of thedesired crystal form, etc.) may also be employed to provide crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid.

In some embodiments,1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is dissolved in heptane at a temperature between about 70° C. andabout reflux temperature. Preferably, the temperature is about 70° C.and the concentration of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid in heptane is between about 0.07 g/mL to about 0.08 g/mL. Thesolution is then cooled to room temperature to provide crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid.

In other embodiments,1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid is dissolved in a mixture of heptane/ethyl acetate (10:1 by volume)at a temperature between about 50° C. and about the reflux temperature,more preferably at a temperature of about 70° C. The concentration of1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid in the heptane/ethyl acetate mixture is between about 0.18 g/mL toabout 0.22 g/mL. The solution is then cooled to between about 0° C. andabout 25° C. to provide crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid.

In yet other embodiments,1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid is dissolved in a mixture of methylcyclohexane/methyl t-butyl ether(the volumetric ratio of methylcyclohexane-to methyl t-butyl etherbetween about 5:1 to about 20:1, preferably, around 10:1) at atemperature between about 20 and about 40° C. and the concentration of1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid in the methylcyclohexane/methyl t-butyl ether mixture is betweenabout 0.1 g/mL to about 0.25 g/mL. The solution is then cooled tobetween about 0° C. and about 25° C. to provide crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid.

5.3 Therapeutic Uses

Crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof may be administered to apatient, preferably a human, suffering from epilepsy, pain (especially,neuropathic pain and muscular and skeletal pain), post-herpeticneuralgia, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic,inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders, hot flashes, restless legs syndrome, urinary incontinence orethanol withdrawal syndrome. Further, in certain embodiments,crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof are administered to apatient, preferably a human, as a preventative measure against variousdiseases or disorders. Crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof may be administered as apreventative measure to a patient having a predisposition for epilepsy,pain (especially, neuropathic pain and muscular and skeletal pain),post-herpetic neuralgia, depression, anxiety, psychosis, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,panic, inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders, hot flashes, restless legs syndrome, urinaryincontinence or ethanol withdrawal syndrome. Accordingly, crystallineforms of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid and/or pharmaceutical compositions thereof may be used forthe prevention of one disease or disorder and concurrently treatinganother (e.g., prevention of psychosis while treating gastrointestinaldisorders; prevention of neuropathic pain while treating ethanolwithdrawal syndrome).

The suitability of crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof in treating epilepsy,pain (especially, neuropathic pain and muscular and skeletal pain),post-herpetic neuralgia, depression, anxiety, psychosis, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,panic, inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders, hot flashes, restless legs syndrome, urinaryincontinence or ethanol withdrawal syndrome may be determined by methodsknown in the art (e.g., Satzinger et al., U.S. Pat. No. 4,024,175;Satzinger et al., U.S. Pat. No. 4,087,544; Woodruff, U.S. Pat. No.5,084,169; Silverman et al., U.S. Pat. No. 5,563,175; Singh, U.S. Pat.No. 6,001,876; Horwell et al., U.S. Pat. No. 6,020,370; Silverman etal., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No. 6,103,932;Silverman et al., U.S. Pat. No. 6,117,906; Silverman, InternationalPublication No. WO 92/09560; Silverman et al., International PublicationNo. WO 93/23383; Horwell et al., International Publication No. WO97/29101, Horwell et al., International Publication No. WO 97/33858;Horwell et al., International Publication No. WO 97/33859; Bryans etal., International Publication No. WO 98/17627; Guglietta et al.,International Publication No. WO 99/08671; Bryans et al., InternationalPublication No. WO 99/21824; Bryans et al., International PublicationNo. WO 99/31057; Magnus-Miller et al., International Publication No. WO99/37296; Bryans et al., International Publication No. WO 99/31075;Bryans et al., International Publication No. WO 99/61424; Pande,International Publication No. WO 00/23067; Bellioti, InternationalPublication No. WO 00/31020; Bryans et al., International PublicationNo. WO 00/50027; and Bryans et al., International Publication No. WO02/00209). Crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof may be used to treat orprevent epilepsy, pain (especially, neuropathic pain and muscular andskeletal pain), post-herpetic neuralgia, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, panic, inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders, hot flashes, restless legs syndrome, urinaryincontinence or ethanol withdrawal syndrome using known proceduresdescribed in the art (see references above).

The compound disclosed herein, may be more efficacious than the parentdrug molecule (e.g., gabapentin or other GABA analog) in treating orpreventing epilepsy, pain (especially, neuropathic pain and muscular andskeletal pain), post-herpetic neuralgia, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, panic, inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders, hot flashes, restless legs syndrome, urinaryincontinence or ethanol withdrawal syndrome because the disclosedcompound may require less time to reach a therapeutic concentration inthe blood, i.e., the compound disclosed herein has a shorter t_(max)than gabapentin when taken orally. Without wishing to bound by theory,it is believed that the compound disclosed herein is absorbed from thegastrointestinal lumen into the blood by a different mechanism than thatby which gabapentin and other known GABA analogs are absorbed. Forexample, gabapentin is believed to be actively transporter across thegut wall by a carrier transporter localized in the human smallintestine. The gabapentin transporter is easily saturated which meansthat the amount of gabapentin absorbed into the blood is notproportional to the amount of gabapentin that is administer orally,since once the transport mechanism is saturated, further absorption ofgabapentin does not occur to any significant degree. In comparison togabapentin, the compound disclosed herein, is absorbed across the gutwall along a greater portion of the gastrointestinal tract, includingthe colon.

Because the compound disclosed herein can be formulated in sustainedrelease formulations which provides for sustained release over a periodof hours into the gastrointestinal tract and particularly, releasewithin the colon,1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid may also be more efficacious than gabapentin in treating orpreventing epilepsy, pain (especially, neuropathic pain and muscular andskeletal pain), post-herpetic neuralgia, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, panic, inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders, hot flashes, restless legs syndrome, urinaryincontinence or ethanol withdrawal syndrome. The ability of the compounddisclosed herein to be used in sustained release oral dosage formsreduces the dosing frequency necessary for maintenance of atherapeutically effective drug concentration in the blood.

5.4 Modes of Administration

Crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof may be advantageouslyused in human medicine. As previously described, crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof are useful for thetreatment or prevention of epilepsy, pain (especially, neuropathic painand muscular and skeletal pain), post-herpetic neuralgia, depression,anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, panic, inflammatory disease (i.e.,arthritis), insomnia, gastrointestinal disorders, hot flashes, restlesslegs syndrome, urinary incontinence or ethanol withdrawal syndrome.

When used to treat or prevent the above disease or disorders,crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof may be administered orapplied singly, or in combination with other agents. Crystalline formsof 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid and/or pharmaceutical compositions thereof may also beadministered or applied singly or in combination with otherpharmaceutically active agents, including other GABA analogs.

Methods of treatment and prophylaxis are provided by administration to apatient of a therapeutically effective amount of a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof. The patient may be ananimal, is more preferably, a mammal, and most preferably, a human.

Crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof, are preferablyadministered orally. Crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof may also be administeredby any other convenient route, for example, by infusion or bolusinjection, by absorption through epithelial or mucocutaneous linings(e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administrationcan be systemic or local. Various delivery systems are known, (e.g.,encapsulation in liposomes, microparticles, microcapsules, capsules,etc.) that can be used to administer crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof. Methods ofadministration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes or skin.

In some embodiments, crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof can be delivered viasustained release systems, preferably, oral sustained release systems.In one embodiment, a pump may be used (Langer, supra; Sefton, 1987, CRCCrit Ref. Biomed. Eng. 14:201; Saudek et al., 1989, N. Engl. J. Med.321:574).

In other embodiments, polymeric materials can be used (“MedicalApplications of Controlled Release,” Langer and Wise (eds.), CRC Pres.,Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,” Drug ProductDesign and Performance, Smolen and Ball (eds.), Wiley, New York (1984);Langer et al., 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; seealso Levy et al., 1985, Science 228: 190; During et al., 1989, Ann.Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105). In stillother embodiments, polymeric materials are used for oral sustainedrelease delivery. Polymers include, for example, sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (preferably,hydroxypropylmethylcellulose). Other cellulose ethers have beendescribed (Alderman, Int. J. Pharm. Tech. & Prod. Mfr. 1984, 5(3) 1-9).Factors affecting drug release are well known to the skilled artisan andhave been described in the art (Bamba et al., Int. J. Pharm. 1979, 2,307).

In other embodiments, enteric-coated preparations can be used for oralsustained release administration. Coating materials include, forexample, polymers with a pH-dependent solubility (i.e., pH-controlledrelease), polymers with a slow or pH-dependent rate of swelling,dissolution or erosion (i.e., time-controlled release), polymers thatare degraded by enzymes (i.e., enzyme-controlled release) and polymersthat form firm layers that are destroyed by an increase in pressure(i.e., pressure-controlled release).

In still other embodiments, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.2000, 26:695-708). In some embodiments, OROS™ osmotic devices are usedfor oral sustained release delivery devices (Theeuwes et al., U.S. Pat.No. 3,845,770; Theeuwes et al., U.S. Pat. No. 3,916,899).

In yet other embodiments, a controlled-release system can be placed inproximity of the target of crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof, thus requiring only afraction of the systemic dose (e.g., Goodson, in “Medical Applicationsof Controlled Release,” supra, vol. 2, pp. 115-138 (1984)). Othercontrolled-release systems discussed in Langer, 1990, Science249:1527-1533 may also be used.

Crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof preferably, providegabapentin upon in vivo administration to a patient. While not wishingto bound by theory, the promoiety of crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof may be cleaved eitherchemically and/or enzymatically. One or more enzymes present in thestomach, intestinal lumen, intestinal tissue, blood, liver, brain or anyother suitable tissue of a mammal may cleave the promoiety ofcrystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof. The mechanism ofcleavage is not important. Preferably, gabapentin formed by cleavage ofpromoieties from the crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof does not containsubstantial quantities of γ-lactam contaminant (preferably, less than0.5% by weight, more preferably, less than 0.2% by weight, mostpreferably less than 0.1% by weight) which is formed by intramolecularcyclization of the γ amino group with the carboxyl functionality. Theextent of lactam formation from crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof may be assessed usingstandard in vitro analytical methods.

While not wishing to bound by theory, the promoiety of crystalline formsof 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid and/or pharmaceutical compositions thereof may be cleavedprior to absorption by the gastrointestinal tract (e.g., within thestomach or intestinal lumen) and/or after absorption by thegastrointestinal tract (e.g., in intestinal tissue, blood, liver orother suitable tissue of a mammal). If the promoiety of crystallineforms of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid and/or pharmaceutical compositions thereof is cleaved priorto absorption by the gastrointestinal tract, gabapentin may be absorbedinto the systemic circulation conventionally (e.g., via the largeneutral amino acid transporter located in the small intestine). If thepromoiety of crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof are cleaved afterabsorption by the gastrointestinal tract, this GABA analog prodrug maybe absorbed into the systemic circulation either by passive diffusion,active transport or by both passive and active processes.

If the promoiety of crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof is cleaved afterabsorption by the gastrointestinal tract, this GABA analog prodrug mayhave the opportunity to be absorbed into the systemic circulation fromthe large intestine. In this situation, crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof are preferablyadministered as sustained release systems. In some embodiments,crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof are delivered by oralsustained release administration. Preferably, in these embodiments,crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof are administered twiceper day (more preferably, once per day).

5.5 Pharmaceutical Compositions

The present pharmaceutical compositions contain a therapeuticallyeffective amount of a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid together with a suitable amount of a pharmaceutically acceptablevehicle, so as to provide the form for proper administration to apatient. When administered to a patient, crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and pharmaceutically acceptable vehicles are preferably sterile.Water is a preferred vehicle when a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is administered intravenously. Saline solutions and aqueousdextrose and glycerol solutions can also be employed as liquid vehicles,particularly for injectable solutions. Suitable pharmaceutical vehiclesalso include excipients such as starch, glucose, lactose, sucrose,gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerolmonostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol, etc. The present compositions, ifdesired, can also contain minor amounts of wetting or emulsifying agentsor pH buffering agents. In addition, auxiliary, stabilizing, thickening,lubricating and coloring agents may be used.

In some embodiments, the pharmaceutical compositions of crystallineforms of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid are free of lactam side products formed by intramolecularcyclization. In other embodiments, the pharmaceutical compositions ofcrystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid are stable to extended storage (preferably, greater than one year)without substantial lactam formation (preferably, less than 0.5% lactamby weight, more preferably, less than 0.2% lactam by weight, mostpreferably, less than 0.1% lactam by weight).

Pharmaceutical compositions comprising crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid may be manufactured by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or lyophilizing processes. Pharmaceutical compositions may beformulated in conventional manner using one or more physiologicallyacceptable carriers, diluents, excipients or auxiliaries, whichfacilitate processing of crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.

The present pharmaceutical compositions can take the form of solutions,suspensions, emulsion, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In some embodiments, the pharmaceuticallyacceptable vehicle is a capsule (e.g., Grosswald et al., U.S. Pat. No.5,698,155). Other examples of suitable pharmaceutical vehicles have beendescribed in the art (see Remington's Pharmaceutical Sciences,Philadelphia College of Pharmacy and Science, 19th Edition, 1995).Compositions of crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid are preferably formulated for oral delivery, particularly for oralsustained release administration.

Pharmaceutical compositions for oral delivery may be in the form oftablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions may contain one or more optional agents, forexample, sweetening agents such as fructose, aspartame or saccharin,flavoring agents such as peppermint, oil of wintergreen or cherrycoloring agents and preserving agents, to provide a pharmaceuticallypalatable preparation. Moreover, where in tablet or pill form, thepharmaceutical compositions may be coated to delay disintegration andabsorption in the gastrointestinal tract, thereby providing a sustainedaction over an extended period of time. Selectively permeable membranessurrounding an osmotically active driving compound are also suitable fororally administering the compounds and compositions disclosed herein. Inthese later platforms, fluid from the environment surrounding thecapsule is imbibed by the driving compound, which swells to displace theagent or agent composition through an aperture. These delivery platformscan provide an essentially zero order delivery profile as opposed to thespiked profiles of immediate release formulations. A time delay materialsuch as glycerol monostearate or glycerol stearate may also be used.Oral compositions can include standard vehicles such as mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, etc. Such vehicles are preferably of pharmaceuticalgrade.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol) oils, alcohols, slightly acidic buffersbetween pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at betweenabout 5 mM to about 50 mM), etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines and the likemay be added.

Pharmaceutical compositions for administration via other routes may alsobe contemplated. For buccal administration, the compositions may takethe form of tablets, lozenges, etc. formulated in conventional manner.Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include acrystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane aceticacid with a pharmaceutically acceptable vehicle. Preferably, thepharmaceutically acceptable vehicle is a liquid such as alcohol, water,polyethylene glycol or perfluorocarbon. Optionally, another material maybe added to alter the aerosol properties of the solution or suspensionof the compounds disclosed herein. Preferably, this material is liquidsuch as an alcohol, glycol, polyglycol or a fatty acid. Other methods offormulating liquid drug solutions or suspension suitable for use inaerosol devices are known to those of skill in the art (see, e.g.,Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611).A crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid may also be formulated in rectal or vaginal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides. In additionto the formulations described previously, a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid may also be formulated as a depot preparation. Such long actingformulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid may be formulated with suitable polymeric or hydrophobic materials(for example, as an emulsion in an acceptable oil) or ion exchangeresins, or as sparingly soluble derivatives, for example, as a sparinglysoluble salt.

In some embodiments, a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is formulated as a pure active agent. In other embodiments, acrystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is formulated as a mixture with other crystalline forms of-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid.

5.6 Dosages

A crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof, will generally be usedin an amount effective to achieve the intended purpose. For use to treator prevent diseases or disorders such as epilepsy, pain (especially,neuropathic pain and muscular and skeletal pain), depression, anxiety,psychosis, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, panic, inflammatory disease (i.e.,arthritis), insomnia, gastrointestinal disorders, hot flashes, restlesslegs syndrome, urinary incontinence or ethanol withdrawal syndrome thecrystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof are administered orapplied in a therapeutically effective amount.

The amount of a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof that will be effectivein the treatment of a particular disorder or condition disclosed hereinwill depend on the nature of the disorder or condition, and can bedetermined by standard clinical techniques known in the art aspreviously described. In addition, in vitro or in vivo assays mayoptionally be employed to help identify optimal dosage ranges. Theamount of a crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof administered will, ofcourse, be dependent on, among other factors, the subject being treated,the weight of the subject, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician.

For example, the dosage may be delivered in a pharmaceutical compositionby a single administration, by multiple applications or controlledrelease. In some embodiments, the crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof are delivered by oralsustained release administration. Preferably, in these embodiments, thecrystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof are administered twiceper day (more preferably, once per day). Dosing may be repeatedintermittently, may be provided alone or in combination with other drugsand may continue as long as required for effective treatment of thedisease state or disorder.

In some embodiments, the dose of the crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof may be adjusted toprovide between about 500 mg/day and about 7000 mg/day of prodrug(equivalent to about 260 mg/day and about 3600 mg/day of gabapentin).Dosage ranges may be readily determined by methods known to the skilledartisan.

The crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof are preferably assayedin vitro and in vivo, for the desired therapeutic or prophylacticactivity, prior to use in humans. Preferably, a therapeuticallyeffective dose of a crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof described herein willprovide therapeutic benefit without causing substantial toxicity.Toxicity of crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof may be determined usingstandard pharmaceutical procedures and may be readily ascertained by theskilled artisan. The dose ratio between toxic and therapeutic effect isthe therapeutic index. The dosage of crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof described herein willpreferably be within a range of circulating concentrations that includean effective dose with little or no toxicity.

5.7 Combination Therapy

In certain embodiments, crystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof can be used incombination therapy with at least one other therapeutic agent. Thecrystalline forms of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and/or pharmaceutical compositions thereof and the othertherapeutic agent can act additively or, more preferably,synergistically. In some embodiments, a pharmaceutical compositioncomprising a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is administered concurrently with the administration of anothertherapeutic agent, which can be part of the same pharmaceuticalcomposition as the crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid or a different pharmaceutical composition. In other embodiments, apharmaceutical composition comprising a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid is administered prior or subsequent to administration of anothertherapeutic agent. For example, a crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid may be administered in combination with an amorphous form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, another crystalline form of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid, gabapentin or pregabalin.

6. EXAMPLES

The following examples describe in detail the preparation of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid and a crystalline form thereof. It will be apparent to thoseskilled in the art that many modifications, both to materials andmethods, may be practiced without departing from the scope of theinvention.

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, the generally acceptedmeaning applies.

Atm=atmosphere

Boc=tert-butyloxycarbonyl

Cbz=carbobenzyloxy

DCC=dicyclohexylcarbodiimide

DMAP=4-N,N-dimethylaminopyridine

DMF=N,N-dimethylformamide

DMSO=dimethylsulfoxide

Fmoc=9-fluorenylmethyloxycarbonyl

gram

hour

HPLC=high pressure liquid chromatography

liter

LC/MS=liquid chromatography/mass spectroscopy

molar

min=minute

mL=milliliter

mmol=millimoles

NHS=N-hydroxysuccinimide

THF=tetrahydrofuran

TFA=trifluoroacetic acid

TLC=thin layer chromatography

TMS=trimethylsilyl

μL=microliter

μM=micromolar

v/v=volume to volume

6.1 Example 1:1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid Via Trimethylsilyl Ester Intermediate Step A:1-{[(α-Chloroethoxy)carbonyl]aminomethyl}-1-Cyclohexane Acetic Acid

In a 5-liter, 3-neck, round bottom flask containing dichloromethane (1.6L) is added gabapentin (120.4 g, 0.704 mol) followed by triethylamine(294 mL, 2.11 mol). Chlorotrimethylsilane (178 mL, 1.40 mol) is slowlyadded while maintaining the reaction temperature below 15° C. and theresulting suspension is stirred for 30 min. 1-Chloroethyl chloroformate(100 g, 0.704 mol) is then added slowly while maintaining thetemperature below 15° C. After the addition is complete, additionaltriethylamine (88 mL, 0.63 mol) is added and the resulting suspension isstirred at room temperature for 30 min. The resulting silyl ester isconverted via acidic work-up to the corresponding acid by washing thereaction mixture with water (2×1 L), followed by 1N HCl (2×2 L) thenbrine (2×500 mL). After drying over anhydrous sodium sulfate and removalof the solvent in vacuo, the crude product (190 g) is obtained as anorange oil and used in Step B without further purification. ¹H NMR(CDCl₃, 400 MHz): δ 1.41-1.57 (m, 10H), 1.78 (d, 3H), 2.33 (s, 2H), 3.27(d, 2H), 5.42 (br. s, 1H), 6.55 (q, 1H).

Step B: 1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid

To a 3-liter, 3-neck, round bottom flask is added isobutyric acid (254g, 2.9 mol) followed by triethylamine (395 ml, 2.84 mol). The reactionmixture is cooled to room temperature and a solution of crude acid fromthe above reaction step (190 g, 0.69 mol) in dichloromethane (80 mL) isadded in a controlled fashion while maintaining the temperature below30° C. The resulting pale yellow solution is stirred overnight. Thereaction mixture is then diluted with one volume of dichloromethane andwashed with water (6×500 mL), aqueous potassium bicarbonate (3×500 mL),and brine (2×500 mL). After drying over anhydrous sodium sulfate,removal of the solvent in vacuo affords the crude product as a dark redoil (87 g). A portion (35 g) of this product is loaded onto an 800 gBiotage™ normal phase silica gel flash column and eluted with 40%diethyl ether in hexane (6 L), which after removal of the solvent invacuo affords the product as a colorless oil (13.5 g). This is repeatedwith a second 35 g portion of crude product yielding a further 13.5 g of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid. A sample of the product (25 g) is recrystallized by dissolution inheptane (325 mL) at 70° C., followed by slow cooling to roomtemperature. The white crystalline product (23 g) is isolated byfiltration. Melting point: 63-64° C.

6.2 Example 2:1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid via Allyl Ester Intermediate

Step A: Allyl 1-Aminomethyl-1-Cyclohexane Acetate Hydrochloride

A dry 3 L, three-neck, round-bottomed flash fitted with a magneticstirring bar and a 500 mL pressure-equalizing addition funnel is flushedwith nitrogen gas. The flask is charged with gabapentin (171 g, 1.0 mol)and allyl alcohol (1 L, 852 g, 14.6 mol) and the entire mixture iscooled to 0° C. in an ice-water bath. Thionyl chloride (225 mL, 360 g,3.0 mol) is added dropwise over a period of 1 h to the stirred solution.The reaction mixture is allowed to stir at room temperature for 16 h,then is diluted with ethyl ether (2 L) and cooled to 0° C. whilestirring. After several minutes white crystals form, which are collectedby filtration. The crude product is recrystallized from a 1/3 (v/v)mixture of ethanol and ethyl ether (2 L) to give the product as a whitesolid (220 g 88%). m.p.: 138-142° C. ¹H NMR (CD₃OD, 400 MHz): δ1.36-1.54 (m, 10H), 2.57 (s, 2H), 3.05 (s, 2H), 4.61 (d, J=6 Hz, 2H),5.22 (dd, J₁=10.4 Hz, J₂=1.2 Hz, 1H), 5.33 (dd, J₁=17.2 Hz, J₂=1.4 Hz,1H), 5.90-6.00 (m, 1H). MS (ESI) m/z 212.0 (M−Cl)⁺.

Step B: Allyl 1-{[(α-Chloroethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetate

To a solution of the above hydrochloride salt (220 g, 0.89 mol) indichloromethane (1 L) is slowly added 1-chloroethyl chloroformate (101.7mL, 132.3 g, 0.92 mol). The reaction mixture is cooled to 0° C. and4-methylmorpholine (205 mL, 188.9 g, 1.87 mol) is slowly added over aperiod of 1 h while maintaining a temperature of less than 10° C. Theresulting turbid solution is stirred at room temperature for 1 h.Ethanol (150 mL) is added and the reaction mixture is stirred at roomtemperature for 1 h. The reaction mixture is then diluted with ether(2.5 L), washed with water (1 L) and brine (1 L). The organic phase isdried over sodium sulfate and concentrated to give the title compound asa light yellow viscous liquid (282 g, 100%). ¹H NMR (CDCl₃, 400 MHz): δ1.35-1.58 (m, 10H), 1.78 (d, J=5.6 Hz, 3H), 2.32 (s, 2H), 3.22 (d, J=6.8Hz, 2H), 4.57 (d, J=5.6 Hz, 2H), 5.25 (dd, J₁=10.4 Hz, J₂=1 Hz, 1H),5.32 (dd, J₁=17.2 Hz, J₂=1.6 Hz, 1H), 5.52 (br, 1H, NH), 5.90-5.94 (m,1H), 6.54 (q, J=5.6 Hz, 1H).

Step C: Allyl1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane Acetate

To a mixture of isobutyric acid (432 mL, 391.5 g, 4.4 mol) and4-methylmorpholine (488 mL, 449 g, 4.4 mol) is added a solution of thechlorocarbamate from the previous step (282 g, 0.88 mol) in isobutyricacid (432 mL, 391.5 g, 4.4 mol). The addition occurs at 0° C. over aperiod of 30 min. The resulting turbid solution is stirred at roomtemperature for 16 h. The reaction mixture is diluted with ether (2.5 L)and washed with water (3×500 mL) followed by 10% aqueous potassiumbicarbonate (6×500 mL) then brine (500 mL). The organic phase is driedover sodium sulfate and concentrated to yield the title compound as aviscous liquid (328 g, 100%). ¹H NMR (CDCl₃, 400 MHz): δ 1.15 (d, J=7.2Hz, 6H), 1.35-1.58 (m, 10H), 2.31 (s, 2H), 2.51 (m, 1H), 3.19 (d, J=5.6Hz, 2H), 4.56 (d, J=5.6 Hz, 2H), 5.24 (dd, J₁=10 Hz, J₂=1 Hz, 1H), 5.32(dd, J₁=17 Hz, J₂=1.2 Hz, 1H), 5.35 (br, 1H), 5.84-5.94 (m, 1H), 6.78(q, J=5.6 Hz, 1H). MS (ESI) m/z 392.24 (M+H)⁺.

Step D: Deprotection of Allyl1-{[(α-Isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-Cyclohexane Acetate

To a stirred suspension of ammonium formate (112 g, 1.7 mol) in ethanol(500 mL) is added the above allyl ester (328 g, 0.88 mol) together with10% Pd/C (15 g) under a nitrogen atmosphere. After 6 h, the reactionmixture is worked-up by filtering off the catalyst. The catalyst iswashed with ethanol (2×250 mL) and the filtrates are combined andevaporated. The crude product is dissolved in ether (2 L) and theorganic phase is washed with 2N HCl (2×2 L) to convert the ammonium saltinto the acid form, followed by washing with water (1 L) and brine (1L). The ether layer is dried over sodium sulfate and concentrated togive the crude product as a viscous liquid (240 g, 82%).

Step E: Crystallization of1-{[(α-Isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-Cyclohexane AceticAcid

A 3 L round-bottom flask is equipped with a heating oil bath, a nitrogeninlet adapter, an internal thermometer, an overhead mechanical stirrer,and a reflux condenser. The flask is flushed with nitrogen and chargedwith a 1/10 (v/v) mixture of ethyl acetate/heptane (1.2 L) and the crudeproduct from the preceding reaction (240 g). The flask is heated untilthe product dissolves, then cooled according to the following schedule:

Temp (° C.) Time (Internal Entry (min.) temp) Appearance Remarks 1 018.0 Solid in solvent Start heating oil bath 2 10 48 Turbid Slowdissolution of product 4 20 58 Clear solution Turn off oil bath 5 25 60Clear solution Maximum temp. reached 6 45 43 Turbid Compoundcrystallizing 7 60 36 Milky solution Seed with pure ref. material 8 9024 Solid in solution

The flask is then cooled to 4° C. overnight with stirring (coolingimproves the yield). The product is filtered and washed with heptane(2×100 mL), then dried under reduced pressure (25 mm of Hg (0.033 atm))at 30° C. for 18 h to yield1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid (185 g) as a white crystalline solid.

6.3 Example 3: X-Ray Powder Diffraction Analysis of Crystalline1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid

X-ray powder diffractograms (XRPD's) of crystalline samples of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid produced according to Examples 1 and 2 above are measured with aBruker D8 Discover X-ray powder diffractometer using Cu Kα radiation.The instrument is equipped with parallel beam optics and atwo-dimensional HI-STAR area detector. The tube voltage and amperage areset to 40 kV and 40 mA, respectively. The collimated X-ray beam isreduced to a spot size of about 0.5 mm in diameter. The area detector isplaced 15 cm from the center of the goniometer and the angularresolution is approximately 0.033°/pixel. The detector covers a range of35° in 2-theta (2θ) within one frame. The angle between the X-ray beamand the horizontal sample plate is set to 4° and the center of the areadetector is set to an angle of 18°. This geometry allows the measurementof 2-theta from 4.5° to 39.5° within one frame. Typical averaging timeis 3 minutes for each XRPD pattern collected. A corundum sample (NIST1976) is used to calibrate the XRPD instrument. Both samples giveequivalent diffractogram patterns, as illustrated in FIG. 1.

6.4 Example 4: Melting Point and Differential Scanning CalorimetryAnalysis of Crystalline1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid

Melting points of crystalline samples of1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid produced according to Examples 1 and 2 above are measured using anElectrothermal 9200 melting point apparatus and are determined to be63-64° C.

Differential scanning calorimetry (DSC) analysis of crystalline samplesof 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid produced according to Examples 1 and 2 above are measuredusing a Perkin Elmer Series 7 instrument, scanning from 25° C. to 250°C. at a scan rate of 5° C./minute. A test portion of the sample isplaced in an aluminum pan and the cap crimped to eliminate any visibleseam between the cap and the pan. An empty pan is prepared in the samemanner as a blank. The pans are placed in the Differential Scanningcalorimeter. The material is run at the appropriate temperature program(Equilibration at Initial Temp, Isothermal, Ramp Rate, Final Temp) toproduce the thermogram shown in FIG. 2. DSC analysis show an endothermictransition with an onset temperature of 58.3° C. and a ΔH of 72.39 J/g.At the peak endotherm of 63-64° C. the sample visibly melts.

6.5 Example 5:{[(1-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid

To a solution of gabapentin (6.8 g, 0.04 mole) in water (40 mL) is addeda solution of [(1-isobutanoyloxyethoxy)carbonyloxy]succinimide (10 g,0.036 mol) in acetonitrile (40 mL) over a period of 30 minutes. Thereaction is stirred at ambient temperature for 3 hours. The reactionmixture is diluted with methyl tert-butyl ether (200 mL), washed withwater (2×100 mL) and brine (50 mL). The organic phase is separated,dried over anhydrous sodium sulfate, filtered, and concentrated in vacuoto afford the title compound as a white solid (12 g, quantitative).

Crystallization: The solid compound (12 g) is suspended inmethylcyclohexane: methyl tert-butyl ether 10:1 (60 mL). The suspensionis slowly heated up to 50° C. over a period of 30 minutes. The clearsolution is then allowed to cool to room temperature. The turbid mixtureis seeded with 5 mg of the title compound in crystalline form. Themixture is further cooled to 0-4° C. for 2 hours. The solid product isfiltered and washed with methylcyclohexane (2×10 mL) to yield the titlecompound as a white crystalline solid (10 g, 83% yield). The crystallinesolid material has a melting point of about 64-66° C. as measured byopen capillary melting point determination.

Finally, it should be noted that there are alternative ways ofimplementing the present invention. Accordingly, the present embodimentsare to be considered as illustrative and not restrictive, and theinvention is not to be limited to the details given herein, but may bemodified within the scope and equivalents of any claim(s) issuingherefrom. All publications and patents cited herein are incorporated byreference in their entirety.

1.-8. (canceled)
 9. A pharmaceutical composition comprising crystalline1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid having a melting point range of between about 63° C. and about 64°C. as determined by differential scanning calorimetry at a scan rate of5° C./minute and a pharmaceutically acceptable vehicle.
 10. Thepharmaceutical composition of claim 9, wherein the pharmaceuticallyacceptable vehicle is selected from the group consisting of water,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol, andcombinations thereof.
 11. The pharmaceutical composition of claim 9,further comprising wetting/emulsifying agents, pH buffering agents,auxiliary agents, stabilizing agents, lubricating agents, coloringagents, and combinations thereof.
 12. The pharmaceutical composition ofclaim 9, wherein the composition is free of lactam side products formedby intramolecular cyclization.
 13. The pharmaceutical composition ofclaim 12, wherein less than 0.5% lactam by weight is formed within oneyear of storage.
 14. The pharmaceutical composition of claim 9, whereinthe composition is in the form of a solution, suspension, emulsion,tablet, pill, pellet, capsule, powder, sustained-release formulation,suppository, aerosol, spray, lozenge, granule, syrup.
 15. Thepharmaceutical composition of claim 9, wherein the composition is anoral composition in the form of a tablet, lozenge, aqueous or oilysuspension, granule, powder, emulsion, capsule, syrup or elixir.
 16. Thepharmaceutical composition of claim 15, further comprising one or moresweetening agent, flavoring agent, or preserving agent.
 17. Thepharmaceutical composition of claim 15, wherein the tablet or pill iscoated to delay disintegration and absorption in the gastrointestinaltract.
 18. The pharmaceutical composition of claim 15, wherein thesuspension, elixir, or syrup comprises a diluent selected from the groupconsisting of water, saline, alkyelene glycol, polyalkylene glycol, oil,alcohol, buffers with a pH between 4 and 6, and combinations thereof.